The present invention relates to pharmaceutical agents (compounds) which are xcex1Vxcex23 and/or xcex1Vxcex25 integrin antagonists and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by xcex1Vxcex23 and/or xcex1Vxcex25 integrins.
The integrin xcex1Vxcex23 (also known as vitronectin receptor), is a member of the integrin family of heterodimeric transmembrane glycoprotein complexes that mediate cellular adhesion events and signal transduction processes. Integrin xcex1Vxcex23 is expressed in number of cell types and has been shown to mediate several biologically relevant processes, including adhesion of osteoclasts to the bone matrix, vascular smooth muscle cell migration and angiogenesis.
The integrin xcex1Vxcex23 has been shown to play a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis, Paget""s disease, humoral hypercalcemia of malignancy, osteopenia, angiogenesis, including tumor angiogenesis and lymphangiogenesis, retinopathy including macular degeneration, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis artherosclerosis). The compounds of the present invention are xcex1Vxcex23 antagonists and can be used, alone or in combination with other therapeutic agents, in the treatment or modulation of various conditions or disease states described above. Additionally, it has been found that such agents would be useful as antivirals, antifungals and antimicrobials.
The integrin xcex1Vxcex25 is thought to play a role in neovascularization. M. C. Friedlander, et al., Science, 270, 1500-1502 (1995) disclose that a monoclonal antibody for xcex1Vxcex25 inhibits VEFG-induced angiogenesis in the rabbit cornea and the chick chorioallantoic membrane model. Therefore compounds which act as antagonists of the xcex1Vxcex25 integrin will inhibit neovascularization and will be useful for treating and preventing angiogenesis metastasis, tumor growth, macular degeneration and diabetic retionopathy.
Certain compounds may antagonize both the xcex1Vxcex25 and the xcex1Vxcex23 receptor and therefore are referred to as xe2x80x9cmixed xcex1Vxcex25/xcex1Vxcex23 antagonistsxe2x80x9d or xe2x80x9cdual xcex1Vxcex23/xcex1Vxcex25 antagonistsxe2x80x9d. Such dual or mixed antagonists are useful for treating or preventing angiogenesis, tumor metastasis, tumor growth, diabetic retinopathy, macular degeneration, atherosclerosis and osteoporosis
It has been shown that the xcex1Vxcex23 integrin and other xcex1V containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules. Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors. However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides which bind to xcex1Vxcex23 also bind to xcex1Vxcex25, xcex1Vxcex21 and xcex1IIbxcex23. Antagonism of platelet xcex1IIbxcex23 (also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions or disease states associated with the integrin xcex1Vxcex23 it would be beneficial to develop compounds which are selective antagonists of xcex1Vxcex23 as opposed to xcex1IIbxcex23.
Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor.
Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561) have shown that the xcex1Vxcex23 integrin has a biological function in melanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that the integrin xcex1Vxcex23 expressed on human melanoma cells promotes a survival signal, protecting the cells from apoptosis. Mediation of the tumor cell metastatic pathway by interference with the xcex1Vxcex23 integrin cell adhesion receptor to impede tumor metastasis would be beneficial.
Further, with the discovery that xcex1Vxcex23 plays a role in the process of lymphatic dissemination via adhesion of melanoma cells to lymph node by binding the vitronectin receptor (Nip et al., J Clin Invest 1992, 90, 1406), inhibitors of xcex1Vxcex23 may also be useful for making alterations in lymphatic endothelial-tumor cell adhesion, thereby further reducing the potential for tumor metastasis.
Brooks et al (Cell, Vol. 79 (1994) 1157-1164) have demonstrated that antagonists of xcex1Vxcex23 provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) since systemic administration of xcex1Vxcex23 antagonists causes dramatic regression of various histologically distinct human tumors.
The compounds of the present invention are useful for the treatment, including prevention of angiogenic disorders. The term angiogenic disorders include conditions involving abnormal neovascularization. The growth of new blood vessels, or angiogenesis, also contributes to pathological conditions such as diabetic retinopathy including macular degeneration (Adamis et al., Amer. J. Ophthal., Vol. 118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med., Vol. 175, (1992), 1135-1138). Therefore, xcex1Vxcex23 antagonists would be useful therapeutic agents for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571).
It has been reported that the cell surface receptor xcex1Vxcex23 is the major integrin on osteoclasts responsible for attachment to bone (for a review, see Rodan and Rodan, 1997, J. Endocrinol. 154, S47, Nakamura et al., J. Cell Science, 1999 112, 3985). Osteoclasts cause bone resorption and when such bone resorbing activity exceeds bone forming activity it leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of xcex1Vxcex23 have been shown to be potent inhibitors of osteoclastic activity both in vitro (Sato et al., J. Cell. Biol., Vol. 111 (1990) 1713-1723) and in vivo (Fisher et al., Endocrinology, Vol. 132 (1993) 1411-1413). Antagonism of xcex1Vxcex23 leads to decreased bone resorption and therefore restores a normal balance of bone forming and resorbing activity. Thus it would be beneficial to provide antagonists of osteoclast xcex1Vxcex23 which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis.
The role of the xcex1Vxcex23 integrin in smooth muscle cell migration also makes it a therapeutic target for prevention or inhibition of neointimal hyperplasia which is a leading cause of restenosis after vascular procedures (Choi et al., J. Vasc. Surg. Vol. 19(1) (1994)125-34). Prevention or inhibition of neointimal hyperplasia by pharmaceutical agents to prevent or inhibit restenosis would be beneficial.
White (Current Biology, Vol. 3(9)(1993) 596-599) has reported that adenovirus uses xcex1Vxcex23 for entering host cells. The integrin appears to be required for endocytosis of the virus particle and may be required for penetration of the viral genome into the host cell cytoplasm. Thus compounds which inhibit xcex1Vxcex23 would find usefulness as antiviral agents.
The compounds of this invention are 1) xcex1Vxcex23 integrin antagonists; or 2) xcex1Vxcex25 integrin antagonists; or 3) mixed or dual xcex1Vxcex23/xcex1Vxcex25 antagonists. The present invention includes compounds which inhibit the respective integrins and also includes pharmaceutical compositions comprising such compounds. The present invention further provides for methods for treating or preventing conditions mediated by the xcex1Vxcex23 and/or xcex1Vxcex23 receptors in a mammal in need of such treatment comprising administering a therapeutically effective amount of the compounds of the present invention and pharmaceutical compositions of the present invention. Administration of such compounds and compositions of the present invention inhibits angiogenesis, tumor metastasis, tumor growth, osteoporosis, Paget""s disease, humoral hypercalcemia of malignancy, retinopathy, macular degeneration, arthritis, periodontal disease, smooth muscle cell migration, including restenosis and artherosclerosis, and viral diseases.
Further, it has been found that the selective antagonism of the xcex1Vxcex23 integrin is desirable in that the xcex1Vxcex26 integrin may play a role in normal physiological processes of tissue repair and cellular turnover that routinely occur in the skin and pulmonary tissue, and xcex1Vxcex28 may play a role in the regulation of growth in the human pathway. Therefore, compounds which selectively inhibit the xcex1Vxcex23 integrin as opposed to the xcex1Vxcex26 and/or the xcex1Vxcex28 integrin have reduced side-effects associated with inhibition of the xcex1Vxcex26 and/or the xcex1Vxcex28 integrin. It is therefore another object of the present invention to provide compounds that are selective antagonists of xcex1Vxcex23 and/or xcex1Vxcex25 as opposed to xcex1Vxcex26, and it is yet another object of the present invention to provide compounds that are selective antagonists of CVD3 and/or xcex1Vxcex25 as opposed to xcex1Vxcex28.
The present invention relates to a class of compounds represented by the Formula 1. 
or a pharmaceutically acceptable salt thereof, wherein 
xe2x80x83is a 4-8 membered monocyclic or a 7-12 membered bicyclic ring, optionally containing 1 to 4 heteroatoms, selected from the group consisting of O, N or S; optionally saturated or unsaturated, optionally substituted with one or more substituent selected from the group consisting of alkyl, haloalkyl, aryl, heteroaryl, halogen, alkoxyalkyl, aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl, thioalkyl, amino, alkylamino, arylamino, alkylsulfonamide, acyl, acylamino, sulfone, sulfonamide, allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, carboxamide, cyano, and xe2x80x94(CH2)n COR wherein n is 0-2 and R is hydroxy, alkoxy, alkyl or amino;
A1 is a 5-9 membered monocyclic or 7-14 membered polycyclic heterocycle of the formula 
xe2x80x83containing at least one nitrogen atom and optionally 1 to 4 heteroatoms or groups selected from O, N, S, SO2 or CO; optionally saturated or unsaturated; optionally substituted by one or more Rk selected from the group consisting of hydroxy, alkyl, alkoxy, alkoxyalkyl, thioalkyl, haloalkyl, cyano, amino, alkylamino, halogen, acylamino, sulfonamide and xe2x80x94COR wherein R is hydroxy, alkoxy, alkyl or amino; 
xe2x80x83include the following heterocyclic ring systems containing at least one nitrogen atom: 
xe2x80x83wherein Za is H, alkyl, alkoxy, hydroxy, amine, alkylamine, dialkylamine, carboxyl, alkoxycarbonyl, hydroxyalkyl, halogen or haloalkyl and R1 is H, alkyl, alkoxyalkyl, acyl, haloalkyl or alkoxycarbonyl. More specifically some examples of embodiments include pyridylamino, imidazolylamino, morpholinopyridine, tetrahydronaphthyridine, oxazolylamino, thiazolylamino, pyrimidinylamino, quinoline, isoquinoline, tetrahydroquinoline, imidazopyridine, benzimidazole, pyridone or quinolone.
The following heteroaryls include the ring systems described above. 
For the pyridyl derived heterocycle, the substituents X4 and X5 are selected from the group consisting of H, alkyl, branched alkyl, alkylamino, alkoxyalkylamino, haloalkyl, thioalkyl, halogen, amino, alkoxy, aryloxy, alkoxyalkyl, hydroxy, cyano or acylamino groups. In another embodiment of the invention, the substituents X4 and X5 can be methyl, methoxy, amine, methylamine, trifluoromethyl, dimethylamine, hydroxy, chloro, bromo, fluoro and cyano. X6 may preferentially be H, alkyl, hydroxy, halogen, alkoxy and haloalkyl. Alternately, the pyridyl ring can be fused with a 4-8 membered ring, optionally saturated or unsaturated. Some examples of these ring systems include tetrahydronaphthyridine, quinoline, tetrahydroquinoline, azaquinoline, morpholinopyridine, imidazo-pyridine and the like. The monocyclic ring systems such as imidazole, thiazole, oxazole, pyrazole, and the like, may contain an amino or alkylamino substituent at any position within the ring.
In another embodiment of the present invention, when Z1 of Formula I is CO or SO2, the linkage A1-Z2 of Formula I includes the heterocycle derived ring systems such as: pyridine, imidazole, thiazole, oxazole, benzimidazole, imidazopyridine and the like.
Other heterocycles for A1-Z2 of the present invention include 
wherein X4 is as defined above.
or 
wherein Y1 is selected from the group consisting of Nxe2x80x94R2, O, and S;
R2 is selected from the group consisting of H; alkyl; aryl; hydroxy; alkoxy; cyano; alkenyl; alkynyl; amido; alkylcarbonyl; arylcarbonyl; alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl;
R2 taken together with R7 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, thioalkyl, alkylamino, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl;
or
R2 taken together with R7 forms a 4-12 membered heterocycle containing one or more heteroatom selected from O, N and S optionally unsaturated;
or
R2 taken together with R7 forms a 5 membered heteroaromatic ring fused with a aryl or heteroaryl ring;
R7 (when not taken together with R2) and R8 are independently selected from the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl; amino; alkylamino; hydroxy; alkoxy; arylamino; amido, alkylcarbonyl, arylcarbonyl; alkoxycarbonyl; aryloxy; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl; cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl;
or
NR7 and R8 taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S;
R5 is selected from the group consisting of H and alkyl;
or 
wherein y2 is selected from the group consisting of alkyl; cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles;
Z1 is selected from the group consisting of CH2, CH2O, O, NH, CO, S, SO, CH(OH) and SO2;
Z2 is a 1-5 carbon linker optionally containing one or more heteroatom selected from the group consisting of O, S and N; alternatively Z1-Z2 may further contain a carboxamide, sulfone, sulfonamide, alkenyl, alkynyl, or acyl group;
wherein the carbon and nitrogen atoms of Z1-Z2 are optionally substituted by alkyl, alkoxy, thioalkyl, alkylsulfone, aryl, alkoxyalkyl, hydroxy, alkylamino, heteroaryl, alkenyl, alkynyl, carboxyalkyl, halogen, haloalky or acylamino;
n is an integer 0, 1 or 2;
Rc is selected from the group consisting of hydrogen; alkyl; halogen, hydroxy, nitro, alkoxy, amino, haloalkyl, aryl, heteroaryl, alkoxyalkyl, aminoalkyl, hydroxyalkyl, thioalkyl, alkylamino, arylamino, alkylsulfonylamino, acyl, acylamino, alkylsulfone, sulfonyl, sulfonamide, allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, alkynylalkyl, carboxy, alkoxycarbonyl, carboxamido, cyano, and xe2x80x94(CH2)nCOR wherein n is 0-2 and R is selected from hydroxy, alkoxy, alkyl and amino;
Rd is selected from a group consisting of H, alkyl, hydroxy, aryl, or alkoxy;
X is selected from the group consisting of xe2x80x94CHRexe2x80x94, xe2x80x94NRfxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94, and CO wherein Re is H, lower alkyl, alkoxy, cycloalkyl, alkoxyalkyl, hydroxy, alkynyl, alkenyl, haloalkyl, thioalkyl or aryl; wherein when Re is hydroxy the hydroxy can optionally form a lactone with the carboxylic acid function of the chain; wherein Rf is selected from the group consisting of H, alkyl, aryl, benzyl and haloalkyl;
Y is selected from the group consisting of xe2x80x94CR9xe2x80x94 or xe2x80x94Nxe2x80x94 wherein R9 is selected from the group consisting of H, alkyl, haloalkyl, alkoxyalkyl, alkynyl, aryl, heteroaryl, aralkyl, hydroxy, alkoxy, and carboxyalkyl;
optionally the group Xxe2x80x94Y can contain a moiety selected from the group consisting of acyl, alkyl, sulfonyl, amino, ether, thioether, carboxamido, sulfonamido and olefin;
Rb is X2xe2x80x94Rh wherein X2 is selected from the group consisting of O, S and NRj wherein Rh and Rj are independently selected from the group consisting of H, alkyl, aryl, aralkyl, acyl, and alkoxyalkyl; and
Ra is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl, hydroxyalkyl, alkynyl, alkynylalkyl, alkenylalkyl, haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, carboxyl, amino, alkylamino, alkoxycarbonyl, carboxamido, hydroxy, cyano, alkoxy, thioalkyl, acyclamino, sulfonylamino, alkylsulfonyl, and xe2x80x94(CH2)n CORb wherein n is 0-2 and Rb is as defined above.
It is another object of the invention to provide pharmaceutical compositions comprising compounds of the Formula 1. Such compounds and compositions are useful in selectively inhibiting or antagonizing the xcex1Vxcex23 and/or xcex1Vxcex25 integrins and therefore in another embodiment the present invention relates to a method of selectively inhibiting or antagonizing the xcex1Vxcex23 and/or xcex1Vxcex25 integrin. The invention further involves treating or inhibiting pathological conditions associated therewith such as osteoporosis, humoral hypercalcemia of malignancy, Paget""s disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration and diabetic retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis in a mammal in need of such treatment. Additionally, such pharmaceutical agents are useful as antiviral agents, and antimicrobials. The compounds of the present invention may be used alone or in combination with other pharmaceutical agents.